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Antioxidants & Redox Signaling Jun 2024Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber...
AIMS
Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber hypertrophy due to the lack of strategies to precisely regulate individual oxidants in vivo. In this study, we used tetrathiomolybdate (TM) to dissociate the link between superoxide and H2O2 and thereby to specifically explore the role of superoxide in muscle hypertrophy in C2C12 cells and mice.
RESULTS
TM can linearly regulate intracellular superoxide levels by inhibition of superoxide dismutase 1 (SOD1). A 70% increase in superoxide levels in C2C12 myoblast cells and mice is necessary and sufficient for triggering hypertrophy of differentiated myotubes, and can enhance exercise performance by more than 50% in mice. SOD1 knockout blocks TM-induced superoxide increments and thereby prevents hypertrophy, whereas SOD1 restoration rescues all these effects. Scavenging superoxide with antioxidants abolishes TM-induced hypertrophy and the enhancement of exercise performance, while the restoration of superoxide levels with a superoxide generator promotes muscle hypertrophy independent of SOD1 activity.
INNOVATION AND CONCLUSION
These findings suggest that superoxide is an endogenous initiator of myofiber hypertrophy, and that TM may be used to treat muscle wasting diseases. Our work not only suggests a novel druggable mechanism to increase muscle mass but also provides a tool for precisely regulating superoxide levels in vivo.
PubMed: 38877802
DOI: 10.1089/ars.2024.0595 -
Journal of Bodywork and Movement... Jul 2024The present study aimed to determine the magnitude and intervention time of resistance training required to generate adaptations in the muscle thickness of the... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The present study aimed to determine the magnitude and intervention time of resistance training required to generate adaptations in the muscle thickness of the quadriceps muscle obtained by ultrasound in healthy adults.
METHOD
A systematic review with meta-analysis was conducted on studies recovered from Pubmed, Web of Science, and Scopus databases up to March 2022. The study selection process was carried out by two independent researchers, with the presence of a third researcher in case of disagreements. The methodological quality of the studies was determined with the TESTEX scale, and the risk of bias analysis was determined using Cochrane's RoB 2.0 tool. The meta-analysis used the inverse of the variance with a fixed model, and the effect size was reported by the standardized mean difference (SMD) with a confidence interval of 95%.
RESULTS
Ten studies were included in a meta-analysis. The overall analysis of the studies demonstrated an SMD = 0.35 [95% CI: 0.13-0.56] (P = 0.002), with a low heterogeneity of I = 0% (P = 0.52). No publication bias was detected using a funnel plot followed by Egger's test (P = 0.06). The degree of certainty of the meta-analysis was high using the GRADE tool.
CONCLUSION
We found that resistance training can generate significant average increases of 16.6% in muscle thickness obtained by ultrasound in the quadriceps femoris muscles of healthy adults. However, the subgroup analysis showed that significant effect sizes were only observed after eight weeks of training.
Topics: Humans; Resistance Training; Quadriceps Muscle; Ultrasonography; Muscle Strength
PubMed: 38876638
DOI: 10.1016/j.jbmt.2024.02.007 -
Pharmacological Research Jul 2024Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a...
Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.
Topics: Animals; Heart Failure; Histone-Lysine N-Methyltransferase; Myocytes, Cardiac; Endoplasmic Reticulum Stress; Male; Mice, Inbred C57BL; Humans; Mice, Knockout; Rats; Mice; Cells, Cultured; Cardiomegaly; Rats, Sprague-Dawley; Thrombospondins
PubMed: 38876442
DOI: 10.1016/j.phrs.2024.107263 -
European Journal of Sport Science Jun 2024While significant progress has been made in understanding the resistance training (RT) strategy for muscle hypertrophy increase, there remains limited knowledge about... (Randomized Controlled Trial)
Randomized Controlled Trial
While significant progress has been made in understanding the resistance training (RT) strategy for muscle hypertrophy increase, there remains limited knowledge about its impact on fat mass loss. This study aimed to investigate whether full-body is superior to split-body routine in promoting fat mass loss among well-trained males. Twenty-three participants were randomly assigned to 1 of 2 groups: full-body (n = 11, training muscle groups 5 days per week) and split-body (n = 12, training muscle groups 1 day per week). Both groups performed a weekly set volume-matched condition (75 sets/week, 8-12 repetition maximum at 70%-80 % of 1RM) for 8 weeks, 5 days per week with differences only in the routine. Whole-body and regional fat were assessed using DXA at the beginning and at the end of the study. Full-body RT elicited greater losses compared to split-body in whole-body fat mass (-0.775 ± 1.120 kg vs. +0.317 ± 1.260 kg; p = 0.040), upper-limb fat mass (-0.085 ± 0.118 kg vs. +0.066 ± 0.162 kg; p = 0.019), gynoid fat mass (-0.142 ± 0.230 kg vs. +0.123 ± 0.230 kg; p = 0.012), lower-limb fat mass (-0.197 ± 0.204 kg vs. +0.055 ± 0.328 kg; p = 0.040), and a trend in interaction in android fat mass (-0.116 ± 0.153 kg vs. +0.026 ± 0.174 kg; p = 0.051), with large effects sizes (η ≥ 0.17). This study provides evidence that full-body is more effective in reducing whole-body and regional fat mass compared to split-body routine in well-trained males.
Topics: Humans; Male; Resistance Training; Young Adult; Adult; Body Composition; Adipose Tissue; Muscle, Skeletal; Absorptiometry, Photon
PubMed: 38874955
DOI: 10.1002/ejsc.12104 -
Physiological Reports Jun 2024ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in...
ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology in male mice. Three weeks post-surgery, ERK3, but not ERK4 or p38α, co-immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC-ERK3 than TAC-ERK3 hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC-induced increase in Col1a1 mRNA abundance was diminished in ERK3 hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and "activated" myofibroblasts isolated from adult mouse heart, siRNA-mediated knockdown of ERK3 reduced the TGF-β-induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.
Topics: Animals; Male; Mice; Fibroblasts; Collagen Type I; Collagen Type I, alpha 1 Chain; Myocardium; Mitogen-Activated Protein Kinase 6; Mice, Inbred C57BL; Protein Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins; Mitogen-Activated Protein Kinase 3; Cells, Cultured; Cardiomegaly; Myocytes, Cardiac
PubMed: 38872461
DOI: 10.14814/phy2.16108 -
Journal of Medical Economics 2024Patients with obstructive hypertrophic cardiomyopathy (oHCM) experience significant clinical burden which is associated with a high economic burden. Peak oxygen uptake... (Review)
Review
AIMS
Patients with obstructive hypertrophic cardiomyopathy (oHCM) experience significant clinical burden which is associated with a high economic burden. Peak oxygen uptake (pVO2), measured by cardiopulmonary exercise testing, is used to quantify functional capacity, and has been studied as a primary endpoint in recent clinical trials. This study aimed to gather evidence to consolidate the prognostic value of pVO2 in oHCM and to assess whether it is feasible to predict health outcomes in an economic model based on changes in pVO2.
METHODS
A targeted literature review was conducted in MEDLINE ( PubMed) and Embase databases to identify evidence on the prognostic value of pVO2 as a surrogate health outcome to support future oHCM economic model development. Following screening, study characteristics, population characteristics, and pVO2 prognostic association data were extracted.
RESULTS
A total of 4,687 studies were identified. In total, 3,531 and 538 studies underwent title/abstract and full-text screening, respectively, of which 151 were included and nine of these were in hypertrophic cardiomyopathy (HCM); only three studies focused on oHCM. The nine HCM studies consisted of one systematic literature review and eight primary studies reporting on 27 potentially predictive relationships from a pVO2-based metric with clinical outcomes including all-cause mortality, cardiovascular mortality, sudden cardiac death, transplant, paroxysmal, and permanent atrial fibrillation. pVO2 was described as a predictor of single and composite endpoints, in three and six studies, respectively, with one study reporting on both.
LIMITATIONS
This study primarily uses systemic literature review methods but does not qualify as one due to not entailing parallel reviewers during title-abstract and full-text stages of review.
CONCLUSION
The findings of this study suggest pVO2 is predictive of multiple health outcomes, providing a rationale to use pVO2 in the development of an economic model.
Topics: Humans; Cardiomyopathy, Hypertrophic; Exercise Test; Models, Economic; Oxygen Consumption; Prognosis
PubMed: 38868944
DOI: 10.1080/13696998.2024.2367920 -
Cardiovascular Diabetology Jun 2024The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune...
Y4 RNA fragments from cardiosphere-derived cells ameliorate diabetic myocardial ischemia‒reperfusion injury by inhibiting protein kinase C β-mediated macrophage polarization.
The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune and inflammatory cells, potentially driven by abnormalities in their number and function due to diabetes, may play a significant role. In the present investigation, we simulated myocardial I/R injury by inducing ischemia through ligation of the left anterior descending coronary artery in mice for 40 min, followed by reperfusion for 24 h. Previous studies have indicated that protein kinase Cβ (PKCβ) is upregulated under hyperglycemic conditions and is implicated in the development of various diabetic complications. The Y4 RNA fragment is identified as the predominant small RNA component present in the extracellular vesicles of cardio sphere-derived cells (CDCs), exhibiting notable anti-inflammatory properties in the contexts of myocardial infarction and cardiac hypertrophy. Our investigation revealed that the administration of Y4 RNA into the ventricular cavity of db/db mice following myocardial I/R injury markedly enhanced cardiac function. Furthermore, Y4 RNA was observed to facilitate M2 macrophage polarization and interleukin-10 secretion through the suppression of PKCβ activation. The mechanism by which Y4 RNA affects PKCβ by regulating macrophage activation within the inflammatory environment involves the inhibition of ERK1/2 phosphorylation In our study, the role of PKCβ in regulating macrophage polarization during myocardial I/R injury was investigated through the use of PKCβ knockout mice. Our findings indicate that PKCβ plays a crucial role in modulating the inflammatory response associated with macrophage activation in db/db mice experiencing myocardial I/R, with a notable exacerbation of this response observed upon significant upregulation of PKCβ expression. In vitro studies further elucidated the protective mechanism by which Y4 RNA modulates the PKCβ/ERK1/2 signaling pathway to induce M2 macrophage activation. Overall, our findings suggest that Y4 RNA plays an anti-inflammatory role in diabetic I/R injury, suggesting a novel therapeutic approach for managing myocardial I/R injury in diabetic individuals.
Topics: Animals; Protein Kinase C beta; Myocardial Reperfusion Injury; Macrophages; Disease Models, Animal; Male; Mice, Inbred C57BL; Signal Transduction; Interleukin-10; Mice; Diabetic Cardiomyopathies; Cells, Cultured; Phenotype; Myocytes, Cardiac; Mitogen-Activated Protein Kinase 3; Macrophage Activation; Mitogen-Activated Protein Kinase 1; Ventricular Function, Left; Phosphorylation
PubMed: 38867293
DOI: 10.1186/s12933-024-02247-6 -
Molecular Medicine (Cambridge, Mass.) Jun 2024The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. The...
BACKGROUND
The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. The hypoxic failing heart triggers hypoxia-inducible factor-1α (HIF-1α) actions in the cells sensitized to hypoxia and induces metabolic adaptation by accumulating HIF-1α. Furthermore, soluble monocarboxylic acid transporter protein 1 (MCT1) and mitochondrial pyruvate carrier 1 (MPC1), as key nodes of metabolic adaptation, affect metabolic homeostasis in the failing rat heart. Aerobic exercise training has been reported to retard the progression of HF due to enhancing HIF-1α levels as well as MCT1 expressions, whereas the effects of exercise on MCT1 and MPC1 in HF (hypoxia) remain elusive. This research aimed to investigate the action of exercise associated with MCT1 and MPC1 on HF under hypoxia.
METHODS
The experimental rat models are composed of four study groups: sham stented (SHAM), HF sedentary (HF), HF short-term exercise trained (HF-E1), HF long-term exercise trained (HF-E2). HF was initiated via left anterior descending coronary artery ligation, the effects of exercise on the progression of HF were analyzed by ventricular ultrasound (ejection fraction, fractional shortening) and histological staining. The regulatory effects of HIF-1α on cell growth, MCT1 and MPC1 protein expression in hypoxic H9c2 cells were evaluated by HIF-1α activatort/inhibitor treatment and plasmid transfection.
RESULTS
Our results indicate the presence of severe pathological remodelling (as evidenced by deep myocardial fibrosis, increased infarct size and abnormal hypertrophy of the myocardium, etc.) and reduced cardiac function in the failing hearts of rats in the HF group compared to the SHAM group. Treadmill exercise training ameliorated myocardial infarction (MI)-induced cardiac pathological remodelling and enhanced cardiac function in HF exercise group rats, and significantly increased the expression of HIF-1α (p < 0.05), MCT1 (p < 0.01) and MPC1 (p < 0.05) proteins compared to HF group rats. Moreover, pharmacological inhibition of HIF-1α in hypoxic H9c2 cells dramatically downregulated MCT1 and MPC1 protein expression. This phenomenon is consistent with knockdown of HIF-1α at the gene level.
CONCLUSION
The findings propose that long-term aerobic exercise training, as a non- pharmacological treatment, is efficient enough to debilitate the disease process, improve the pathological phenotype, and reinstate cardiac function in HF rats. This benefit is most likely due to activation of myocardial HIF-1α and upregulation of MCT1 and MPC1.
Topics: Animals; Male; Rats; Disease Models, Animal; Gene Expression Regulation; Heart Failure; Hypoxia-Inducible Factor 1, alpha Subunit; Mitochondrial Membrane Transport Proteins; Monocarboxylic Acid Transporters; Myocytes, Cardiac; Physical Conditioning, Animal; Rats, Sprague-Dawley; Symporters; Up-Regulation
PubMed: 38867145
DOI: 10.1186/s10020-024-00854-3 -
BMC Genomics Jun 2024The skeletal muscle growth rate and body size of Tibetan pigs (TIB) are lower than Large white pigs (LW). However, the underlying genetic basis attributing to these...
BACKGROUND
The skeletal muscle growth rate and body size of Tibetan pigs (TIB) are lower than Large white pigs (LW). However, the underlying genetic basis attributing to these differences remains uncertain. To address this knowledge gap, the present study employed whole-genome sequencing of TIB (slow growth) and LW (fast growth) individuals, and integrated with existing NCBI sequencing datasets of TIB and LW individuals, enabling the identification of a comprehensive set of genetic variations for each breed. The specific and predominant SNPs in the TIB and LW populations were detected by using a cutoff value of 0.50 for SNP allele frequency and absolute allele frequency differences (△AF) between the TIB and LW populations.
RESULTS
A total of 21,767,938 SNPs were retrieved from 44 TIB and 29 LW genomes. The analysis detected 2,893,106 (13.29%) and 813,310 (3.74%) specific and predominant SNPs in the TIB and LW populations, and annotated to 24,560 genes. Further GO analysis revealed 291 genes involved in biological processes related to striated and/or skeletal muscle differentiation, proliferation, hypertrophy, regulation of striated muscle cell differentiation and proliferation, and myoblast differentiation and fusion. These 291 genes included crucial regulators of muscle cell determination, proliferation, differentiation, and hypertrophy, such as members of the Myogenic regulatory factors (MRF) (MYOD, MYF5, MYOG, MYF6) and Myocyte enhancer factor 2 (MEF2) (MEF2A, MEF2C, MEF2D) families, as well as muscle growth inhibitors (MSTN, ACVR1, and SMAD1); KEGG pathway analysis revealed 106 and 20 genes were found in muscle growth related positive and negative regulatory signaling pathways. Notably, genes critical for protein synthesis, such as MTOR, IGF1, IGF1R, IRS1, INSR, and RPS6KA6, were implicated in these pathways.
CONCLUSION
This study employed an effective methodology to rigorously identify the potential genes associated with skeletal muscle development. A substantial number of SNPs and genes that potentially play roles in the divergence observed in skeletal muscle growth between the TIB and LW breeds were identified. These findings offer valuable insights into the genetic underpinnings of skeletal muscle development and present opportunities for enhancing meat production through pig breeding.
Topics: Animals; Polymorphism, Single Nucleotide; Muscle, Skeletal; Swine; Gene Frequency; Muscle Development; Whole Genome Sequencing; Tibet; Genome
PubMed: 38862895
DOI: 10.1186/s12864-024-10508-7 -
NPJ Microgravity Jun 2024Skeletal muscles overcome terrestrial, gravitational loading by producing tensile forces that produce movement through joint rotation. Conversely, the microgravity of...
Skeletal muscles overcome terrestrial, gravitational loading by producing tensile forces that produce movement through joint rotation. Conversely, the microgravity of spaceflight reduces tensile loads in working skeletal muscles, causing an adaptive muscle atrophy. Unfortunately, the design of stable, physiological bioreactors to model skeletal muscle tensile loading during spaceflight experiments remains challenging. Here, we tested a bioreactor that uses initiation and cessation of cyclic, tensile strain to induce hypertrophy and atrophy, respectively, in murine lineage (C2C12) skeletal muscle myotubes. Uniaxial cyclic stretch of myotubes was conducted using a StrexCell® (STB-1400) stepper motor system (0.75 Hz, 12% strain, 60 min day^-1). Myotube groups were assigned as follows: (a) quiescent over 2- or (b) 5-day (no stretch), (c) experienced 2-days (2dHY) or (d) 5-days (5dHY) of cyclic stretch, or (e) 2-days of cyclic stretch followed by a 3-day cessation of stretch (3dAT). Using ß-sarcoglycan as a sarcolemmal marker, mean myotube diameter increased significantly following 2dAT (51%) and 5dAT (94%) vs. matched controls. The hypertrophic, anabolic markers talin and Akt phosphorylation (Thr308) were elevated with 2dHY but not in 3dAT myotubes. Inflammatory, catabolic markers IL-1ß, IL6, and NF-kappaB p65 subunit were significantly higher in the 3dAT group vs. all other groups. The ratio of phosphorylated FoxO3a/total FoxO3a was significantly lower in 3dAT than in the 2dHY group, consistent with elevated catabolic signaling during unloading. In summary, we demonstrated proof-of-concept for a spaceflight research bioreactor, using uniaxial cyclic stretch to produce myotube hypertrophy with increased tensile loading, and myotube atrophy with subsequent cessation of stretch.
PubMed: 38862543
DOI: 10.1038/s41526-023-00320-0